Drugs that have abuse liability in humans typically serve as positive reinforcers to maintain and strengthen behavior leading to their administration in animals and serve as discriminative stimuli controlling two-lever choice behavior. Experiments are being conducted to assess neuropharmacological and behavioral mechanisms underlying drug self-administration behavior and behavior controlled by drugs as discriminative stimuli in rats and monkeys and the ability of pharmacological or behavioral manipulations to modify such behavior. [unreadable] [unreadable] We previously demonstrated that anandamide serves as an effective reinforcer of drug-taking behavior when self-administered intravenously by squirrel monkeys (Justinova et al. 2005). We also showed that methanandamide, a synthetic long-lasting anandamide analog, similarly serves as a reinforcer of drug-taking behavior. Finally, the reinforcing effects of both anandamide and methanandamide were blocked by pretreatment with the cannabinoid CB1 receptor antagonist rimonabant (SR141716). These findings strongly suggest that release of endogenous cannabinoids is involved in brain reward processes and that activation of cannabinoid CB1 receptors by anandamide could be part of the signaling of natural rewarding events. We have now identified (Zangen et al. 2006) two chemical trigger zones for stimulant and rewarding actions of delta-9-tetrahydrocannabinol (THC), the active agent in marijuana and hashish. Microinjections of THC into the posterior ventral tegmental area (VTA) or into the shell of the nucleus accumbens (NAS) increased locomotion, and rats learned to lever-press for injections of THC into each of these regions. Substitution of vehicle for drug or treatment with a cannabinoid CB1 receptor antagonist caused response cessation. Microinjections of THC into the posterior VTA and into the posterior shell of NAS established conditioned place preferences. Injections into the core of the NAS, the anterior VTA, or dorsal to the VTA were ineffective. These findings link the sites of rewarding action of THC to brain regions where such drugs as amphetamines, cocaine, heroin, and nicotine are also thought to have their sites of rewarding action.[unreadable] [unreadable] Accumulating evidence suggests that the endogenous cannabinoid system is involved in the reinforcing effects of heroin. In rats intravenously self-administering heroin, we investigated effects of cannabinoid CB1 receptor agonists and compounds that block transport or metabolism of the endogenous cannabinoid anandamide (Solinas et al., 2005). The natural cannabinoid CB1 receptor agonist THC did not alter self-administration of heroin under a fixed-ratio one schedule. Under a progressive-ratio schedule, however, THC dose-dependently increased the number of heroin injections self-administered per session and the maximal ratio completed (break-point). The synthetic cannabinoid CB1 receptor agonist WIN55,212-2 had effects similar to THC under the progressive-ratio schedule. In contrast, AM404, an inhibitor of transport of anandamide, and URB597, an inhibitor of the enzyme fatty acid amide hydrolase that degrades anandamide, or their combination, did not increase reinforcing efficacy of heroin at any dose tested. Thus, activation of cannabinoid CB1 receptors facilitates the reinforcing efficacy of heroin and this appears to be mediated by interactions between cannabinoid CB1 receptors and mu-opioid receptors and their signaling pathways, rather than by an opioid-induced release of endogenous cannabinoids. [unreadable] [unreadable] Although cannabis possesses addictive properties, there is a continuing debate on the possibility of legalizing cannabis use for medical purposes and decriminalizing its recreational use. Gateway drug hypothesis says that cannabis use could increase the probability of encountering, trying and eventually becoming addicted to other illicit drugs such as heroin or cocaine. The hypothesis can be evaluated by giving rats a history of tetrahydrocannabinol (THC) exposure, then allowing them to self-administer other drugs. Previously (Solinas et al. 2004), we demonstrated that pre-exposure to THC alters some pharmacological effects of heroin that determine frequency of heroin-taking, but offers no support for the hypothesis that pre-exposure to THC alters heroin?s efficacy as a reinforcer. Now we have shown (Panlilio et al., 2006) that THC pre-exposure did not alter the acquisition of cocaine self-administration or the amount of cocaine taken under a fixed-ratio 1 (FR1) schedule, with one response required for each injection. Under a progressive-ratio schedule, with the response requirement increasing exponentially with each injection, cocaine-seeking was significantly reduced in THC-exposed rats, suggesting that the regimen of THC exposure used in the present study caused cocaine to be devalued as a reinforcer. In contrast, in an earlier study that used the same regimen, a history of THC exposure did not alter the value of heroin as a reinforcer under the progressive-ratio schedule, but it increased heroin self-administration under the FR1 schedule. Moreover, we examined how this regimen of THC pre-exposure alters the locomotor effects of cocaine and heroin. THC pre-exposure produced cross-tolerance to the motor-depressant effects of heroin; this may explain the shortened post-injection pauses exhibited by THC-exposed rats under FR1 heroin self-administration. When given cocaine, THC-exposed rats exhibited normal increases in locomotion, but they avoided the center of the open field, suggesting that this THC pre-exposure regimen enhances the anxiogenic effects of cocaine. This enhanced anxiogenic effect-which was verified using another model of anxiety, the light-dark test-may explain the reduced reinforcing value of cocaine observed in THC-exposed rats.[unreadable] [unreadable] We also have conducted a series of experiments (Yasar et al. 2006) to better characterize the pharmacological effects of selegiline (l-deprenyl), which is a selective inhibitor of monoamine-oxidase B (MAO-B) used in the treatment of Parkinson?s disease and proposed as an antidepressant and an aid for cigarette-smoking cessation and treatment of psychostimulant abuse. L-Deprenyl is metabolized in the body to l-methamphetamine and l-amphetamine, suggesting that it may have abuse potential. The current study assessed whether drug-seeking behavior for l-deprenyl or its isomer would be maintained on a second-order schedule and whether l-deprenyl would alter drug-seeking behavior maintained by d-amphetamine if given as a pretreatment. Squirrel monkeys learned to respond on a second-order schedule of reinforcement, where every tenth response was followed by a brief light flash and the first brief light flash after 30 min was paired with intravenous (i.v.) injection of d-amphetamine (0.56 mg/kg), administered over a two-minute period at the end of the session. When responding was stable, saline or different i.v. doses of d-amphetamine, l-deprenyl and d-deprenyl were substituted for 10 days each. Subsequently, monkeys were pretreated with 0.3 or 1.0 mg/kg l-deprenyl i.m. 30-min prior to d-amphetamine baseline sessions. Drug-seeking behavior for d-amphetamine was well maintained on the second-order schedule. D-Deprenyl maintained high rates of drug-seeking behavior similar to d-amphetamine. L-Deprenyl maintained lower rates of responding that were not significantly above saline substitution levels. Pretreatment with l-deprenyl failed to alter drug-seeking behavior maintained by d-amphetamine. These results indicate that d-deprenyl, but not l-deprenyl, may have abuse potential. Under conditions where drug-seeking and drug-taking behavior is actively maintained by d-amphetamine, l-deprenyl, at doses that specifically inhibit MAO-B, may not be effective as a treatment.